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2.
Int J Mol Sci ; 22(2)2021 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-33445675

RESUMO

Mycotoxins are present in everyday diet as common food and feed pollutants. A part of them is still concerned as so-called emerging mycotoxins. Due to the lack of toxicity data, the safety limits and detail molecular mechanism have been not established yet for all of them. Alternariol (AOH), as one of these mycotoxins, produced by Alternaria species, is so far reported as an estrogenic, genotoxic, and immunomodulatory agent; however, its direct effect on human health is not known. Especially, in the case of hormone-dependent tissues which are sensitive to both endogenic, as well as external estrogenic agents, it might be crucial to assess the effect of AOH. Thus, this study evaluated how exposure to AOH affects viability and motility of the human normal mammary gland epithelial in vitro model. We observed that AOH significantly affects viability of cells in a time- and dose-dependent manner. Moreover, the induction of oxidative stress, DNA damage, and cell cycle arrest in the G2/M cell cycle phase was observed. The motility of 184A1 cells was also significantly affected. On the molecular level, AOH induced antioxidative stress response via activation of Nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathway agents, as well as decrease in the phosphorylation of protein kinase B (Akt) and p44/42 (ERK 1-2) molecules, indicating that AOH might affect crucial signaling pathways in both physiological and pathophysiological processes in breast tissue.


Assuntos
Mama/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Lactonas/farmacologia , Glândulas Mamárias Humanas/efeitos dos fármacos , Micotoxinas/farmacologia , Alternaria/metabolismo , Mama/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Linhagem Celular , Dano ao DNA/efeitos dos fármacos , Células Epiteliais/metabolismo , Feminino , Fase G2/efeitos dos fármacos , Humanos , Glândulas Mamárias Humanas/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
3.
Cancer Sci ; 112(4): 1603-1613, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33453094

RESUMO

Breast cancer is the leading cause of cancer death in women. Hormone-receptor-positive breast cancer (HR + BC) is the most common pathological type of breast cancer, of which the main treatment method is endocrine therapy. Unfortunately, primary or acquired drug resistance greatly limits its efficacy. In recent years, the newly launched CDK4/6 inhibitors could effectively reverse endocrine resistance in breast cancer. However, considering their expensive price and side effects, it is particularly important to find out effective biomarkers and screen sensitive patients. Here, we found through bioinformatics analysis that high mobility group box 1 (HMGB1) expression increased in endocrine-resistant HR + BC. In clinical specimens, the higher expression of HMGB1 was associated with shorter progression-free survival (PFS) for HR + BC patients with endocrine therapy after surgery. For endocrine-resistant breast cancer, compared with HMGB1-negative patients, HMGB1-positive patients who received CDK4/6 inhibitors treatment benefited more in PFS. Moreover, we demonstrated that HMGB1 promoted tamoxifen resistance by combining with the Toll-like receptor 4 (TLR4) and activating nuclear factor kappa B (NF-κB) pathway. CDK4/6 inhibitors could downregulate the expression of HMGB1 and suppress the TLR4-NF-κB pathway, and in turn reverse tamoxifen resistance. These results illuminated the critical role of HMGB1 in the process of tamoxifen resistance, explained the mechanism of CDK4/6 inhibitors reversing tamoxifen resistance, and suggested the feasibility of HMGB1 as a potential biomarker for screening sensitive patients receiving CDK4/6 inhibitors.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/fisiologia , Proteína HMGB1/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Tamoxifeno/farmacologia , Antineoplásicos Hormonais/farmacologia , Mama/efeitos dos fármacos , Mama/metabolismo , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Células MCF-7 , NF-kappa B/metabolismo , Intervalo Livre de Progressão , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Transdução de Sinais/efeitos dos fármacos
4.
Nat Med ; 27(2): 250-255, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33462450

RESUMO

The impact of single-agent antibodies against programmed death-ligand 1 (PD-L1) as maintenance therapy is unknown in patients with metastatic breast cancer. The SAFIR02-BREAST IMMUNO substudy included patients with human epidermal growth factor receptor type 2 (Her2)-negative metastatic breast cancer whose disease did not progress after six to eight cycles of chemotherapy. Patients (n = 199) were randomized to either durvalumab (10 mg kg-1 every 2 weeks) or maintenance chemotherapy. In the overall population, durvalumab did not improve progression-free survival (adjusted hazard ratio (HR): 1.40, 95% confidence interval (CI): 1.00-1.96; P = 0.047) or overall survival (OS; adjusted HR: 0.84, 95% CI: 0.54-1.29; P = 0.423). In an exploratory subgroup analysis, durvalumab improved OS in patients with triple-negative breast cancer (TNBC; n = 82; HR: 0.54, 95% CI: 0.30-0.97, P = 0.0377). Exploratory analysis showed that the HR of death was 0.37 (95% CI: 0.12-1.13) for patients with PD-L1+ TNBC (n = 32) and 0.49 (95% CI: 0.18-1.34) for those with PD-L1- TNBC (n = 29). In patients with TNBC, exploratory analyses showed that the HR for durvalumab efficacy (OS) was 0.18 (95% CI: 0.05-0.71; log-rank test, P = 0.0059) in patients with CD274 gain/amplification (n = 23) and 1.12 (95% CI: 0.42-2.99; log-rank test, P = 0.8139) in patients with CD274 normal/loss (n = 32). Tumor infiltration by lymphocytes (CD8, FoxP3 and CD103 expressions) and homologous recombination deficiency did not predict sensitivity to durvalumab in exploratory analyses. This latter finding should be interpreted with caution since only one patient presented a germline BRCA mutation. The present study provides a rationale to evaluate single-agent durvalumab in maintenance therapy in patients with TNBC. Exploratory analyses identified CD274 amplification as a potential biomarker of sensitivity. Maintenance chemotherapy was more effective than durvalumab in patients with hormone receptor-positive and Her2-negative disease.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Antígeno B7-H1/genética , Mama/efeitos dos fármacos , Feminino , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Quimioterapia de Manutenção/métodos , Pessoa de Meia-Idade , Metástase Neoplásica , Intervalo Livre de Progressão , Receptor ErbB-2/genética , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
5.
Med Phys ; 48(3): 1064-1078, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33368354

RESUMO

PURPOSE: An estimated 377 million diagnostic and interventional radiological exams are performed annually in the United States and approximately 4 to 5 billion globally. All use x-ray tubes that emit x-rays over a broad energy band, a technology that is more than a century old. Only a small fraction of the radiation is useful for imaging while the remaining fraction either increases the radiation dose received by the patient or degrades the image. Monochromatic x-rays can provide lower dose images in many of these radiological applications while maintaining or improving image quality. We report the development of the first monochromatic x-ray source suitable for low-dose, high-quality imaging in the clinic and demonstrate its first application and performance with mammography phantoms. METHODS: X-ray fluorescence was used to generate monochromatic x-rays with selectable energies from 18 to 60 keV. This patented technology was incorporated into a laboratory prototype of a monochromatic x-ray mammography system. Image quality was evaluated as a function of radiation dose in standard breast phantoms using the signal-to-noise ratio (SNR) measured for high and low contrast masses and microcalcifications. Spatial imaging properties were assessed from these images as well as from modulation transfer function (MTF) analysis. Measurements using an iodine contrast agent were also performed. The results were compared to those obtained using a commercially available, conventional x-ray mammography system. RESULTS: Our prototype system reduced radiation dose by factors of five to ten times for the same SNRs as obtained from the conventional system. This performance was demonstrated in phantoms simulating a wide range of lesion sizes and microcalcifications in a variety of breast thicknesses. The high SNRs for very thick breast phantoms provide evidence that screening with less breast compression is possible while maintaining image quality. Contrast-enhanced digital mammography (CEDM) with monochromatic x-rays was shown to provide a simpler and more effective technique at substantially lower radiation dose. The MTF value at 20% was 9 lp/mm. CONCLUSIONS: The monochromatic x-ray system is more sensitive for imaging a wide range of breast sizes and compositions than conventional broadband mammography. High image quality and lower dose are its hallmarks. It also makes CEDM much more effective than current methods developed for use with conventional broadband mammography systems.


Assuntos
Mama , Mamografia , Intensificação de Imagem Radiográfica , Mama/efeitos dos fármacos , Feminino , Humanos , Imagens de Fantasmas , Raios X
6.
Pediatrics ; 146(5)2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33106340

RESUMO

OBJECTIVES: Puberty suppression (PS) is a cornerstone of treatment in youth experiencing gender dysphoria. In this study, we aim to inform prescribing professionals on the long-term effects of PS treatment on the development of sex characteristics and surgical implications. METHODS: Participants received PS according to the Endocrine Society guideline at Tanner 2 or higher. Data were collected from adolescents who received PS between 2006 and 2013 and from untreated transgender controls. Data collection pre- and post-PS and before surgery included physical examination and surgical information. RESULTS: In total, 300 individuals (184 transgender men and 116 transgender women) were included. Of these, 43 individuals started PS treatment at Tanner 2/3, 157 at Tanner 4/5, and 100 used no PS (controls). Breast development was significantly less in transgender men who started PS at Tanner 2/3 compared with those who started at Tanner 4/5 and controls. Mastectomy was more frequently omitted or less invasive after PS. In transgender women, the mean penile length was significantly shorter in the PS groups compared with controls (by 4.8 cm [Tanner 2/3] and 2.1 cm [Tanner 4/5]). As a result, the likelihood of undergoing intestinal vaginoplasty was increased (odds ratio = 84 [Tanner 2/3]; odds ratio = 9.8 [Tanner 4/5]). CONCLUSIONS: PS reduces the development of sex characteristics in transgender adolescents. As a result, transgender men may not need to undergo mastectomy, whereas transgender women may require an alternative to penile inversion vaginoplasty. These surgical implications should inform decision-making when initiating PS.


Assuntos
Puberdade/efeitos dos fármacos , Caracteres Sexuais , Pessoas Transgênero , Adolescente , Mama/efeitos dos fármacos , Mama/crescimento & desenvolvimento , Estudos de Casos e Controles , Feminino , Disforia de Gênero , Identidade de Gênero , Procedimentos Cirúrgicos em Ginecologia , Humanos , Masculino , Mastectomia/métodos , Pênis/anatomia & histologia , Pênis/efeitos dos fármacos , Pênis/cirurgia , Exame Físico , Fatores Sexuais , Cirurgia de Readequação Sexual , Vagina/efeitos dos fármacos , Vagina/cirurgia , Adulto Jovem
7.
Anticancer Res ; 40(10): 5883-5893, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988919

RESUMO

BACKGROUND/AIM: Somatic mutations were investigated in 21 patients with postmenopausal estrogen receptor (ER)-positive and human epidermal growth factor receptor-2 (HER-2)-positive (ER+HER2+) breast cancer (BC) treated with neoadjuvant letrozole and lapatinib, to identify their distinct molecular landscape. PATIENTS AND METHODS: We used tissue samples of 21 patients from phase II Neo ALL-IN cohort, and somatic alterations were examined using targeted exome sequencing performed in Foundation Medicine, Inc. (FMI). RESULTS: TP53 (61.9%) and PIK3CA (57.1%) were the two most frequently mutated genes that were inter-correlated (p=0.026). They were associated with unfavorable clinical outcomes, particularly when accompanying PIK3CA mutations at exon 9 in helical domains. Meanwhile, MLL2 alteration was negatively associated with mutations of TP53 or PIK3CA, and it tended to be present in patients with low KI-67 levels and no initial nodal involvement. Moreover, patients with MLL2 mutations numerically showed more favorable overall response rates (ORR) (80% vs. 56.2%) and better 5-year event-free survival (EFS) rates (100% vs. 87.5%) compared to the wild-type. CONCLUSION: Mutations in TP53 and PIK3CA hotspot at exon 9 may be potential negative predictors of ER+HER2+ BC treated with neoadjuvant letrozole and lapatinib, while MLL2 inactivating mutation might confer therapeutic benefit in these patients.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Classe I de Fosfatidilinositol 3-Quinases/genética , Proteínas de Ligação a DNA/genética , Proteínas de Neoplasias/genética , Proteína Supressora de Tumor p53/genética , Idoso , Biomarcadores Tumorais/genética , Mama/efeitos dos fármacos , Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Receptor alfa de Estrogênio/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Lapatinib/administração & dosagem , Letrozol/administração & dosagem , Pessoa de Meia-Idade , Mutação/genética , Intervalo Livre de Progressão , Receptor ErbB-2/genética
8.
Biomolecules ; 10(8)2020 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-32784479

RESUMO

Plant-derived pentacyclic triterpenic acids (TAs) have gained increasing attention due to their multiple biological activities. Betulinic acid (BA) and ursolic acid (UA) modulate diverse pathways in carcinogenesis, offering increased changes of success in refractory cancers, such as triple negative breast cancer (TNBC). The present work aimed to assess the metabolic effects of BA and UA in MDA-MB-231 breast cancer cells (TNBC model), as well as in MCF-10A non-cancer breast epithelial cells, with a view to unveiling the involvement of metabolic reprogramming in cellular responses to these TAs. Cell viability and cell cycle analyses were followed by assessment of changes in the cells exo- and endometabolome through 1H NMR analysis of cell culture medium supernatants, aqueous and organic cell extracts. In MDA-MB-231 cells, BA was suggested to induce a transient upregulation of glucose consumption and glycolytic conversion, tricarboxylic acid (TCA) cycle intensification, and hydrolysis of neutral lipids, while UA effects were much less pronounced. In MCF-10A cells, boosting of glucose metabolism by the two TAs was accompanied by diversion of glycolytic intermediates to the hexosamine biosynthetic pathway (HBP) and the synthesis of neutral lipids, possibly stored in detoxifying lipid droplets. Additionally, breast epithelial cells intensified pyruvate consumption and TCA cycle activity, possibly to compensate for oxidative impairment of pyruvate glycolytic production. This study provided novel insights into the metabolic effects of BA and UA in cancer and non-cancer breast cells, thus improving current understanding of the action of these compounds at the molecular level.


Assuntos
Mama/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Metaboloma/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/metabolismo , Triterpenos/farmacologia , Mama/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ciclo do Ácido Cítrico/efeitos dos fármacos , Células Epiteliais/metabolismo , Feminino , Glucose/metabolismo , Glicólise/efeitos dos fármacos , Hexosaminas/metabolismo , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Metabolômica , Triterpenos Pentacíclicos
9.
Acta Cir Bras ; 35(4): e202000407, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32555938

RESUMO

PURPOSE: To evaluate whether silicone foam implants have a different evolution pattern compared to conventional texture implants. METHODS: Fifty-eight female patients underwent surgery. They were divided into two groups (silicone foam - Lifesil® - and microtexturized silicone - Lifesil®). The evolution was analyzed in postoperative consultations, with physical examination, photographic documentation and filling in a satisfaction questionnaire, in the postoperative period of one month, four months, one year and then annually, up to a maximum of 3 years of follow-up. RESULTS: There were no statistically significant differences in presence of rippling, stretch marks, breast ptosis, capsular contracture and quality of scars. There was a higher rate of patients who were very satisfied with the outcome 360 days after surgery in the group receiving silicone foam implants (p = 0.036). CONCLUSION: In short time, silicone foam envelope implants proved to be as reliable as textured silicone envelope implants, making them an option for augmentation mammoplasty.


Assuntos
Implante Mamário/métodos , Implantes de Mama , Elastômeros de Silicone/uso terapêutico , Adulto , Mama/efeitos dos fármacos , Implante Mamário/efeitos adversos , Implantes de Mama/efeitos adversos , Feminino , Reação a Corpo Estranho/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Satisfação do Paciente , Complicações Pós-Operatórias , Estudos Prospectivos , Reprodutibilidade dos Testes , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
10.
Cancer Causes Control ; 31(9): 827-837, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32476101

RESUMO

PURPOSE: We investigated the associations of aspirin and other non-steroid anti-inflammatory drugs with mammographic breast density (MBD) and their interactions in relation to breast cancer risk. METHODS: This study included 3,675 cancer-free women within the Nurses' Health Study (NHS) and Nurses' Health Study II (NHSII) cohorts. Percent breast density (PD), absolute dense area (DA), and non-dense area (NDA) were measured from digitized film mammograms using a computer-assisted thresholding technique; all measures were square root-transformed. Information on medication use was collected in 1980 (NHS) and 1989 (NHSII) and updated biennially. Medication use was defined as none, past or current; average cumulative dose and frequency were calculated for all past or current users from all bi-annual questionnaires preceding the mammogram date. We used generalized linear regression to quantify associations of medications with MBD. Two-way interactions were examined in logistic regression models. RESULTS: In multivariate analysis, none of the anti-inflammatory medications were associated with PD, DA, and NDA. We found no interactions of any of the medications with PD with respect to breast cancer risk (all p-interactions > 0.05). However, some of the aspirin variables appeared to have positive associations with breast cancer risk limited only to women with PD 10-24% (past aspirin OR 1.56, 95% CI 1.03-2.35; current aspirin with < 5 years of use OR 1.82, 95% CI 1.01-3.28; current aspirin with ≥ 5 years of use OR 1.89, 95% CI 1.26-2.82). CONCLUSIONS: Aspirin and NSAIDs are not associated with breast density measures. We found no interactions of aspirin with MBD in relation to breast cancer risk.


Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Aspirina/administração & dosagem , Densidade da Mama/efeitos dos fármacos , Neoplasias da Mama/epidemiologia , Mama/diagnóstico por imagem , Adulto , Mama/citologia , Mama/efeitos dos fármacos , Mama/patologia , Neoplasias da Mama/diagnóstico por imagem , Estudos de Coortes , Feminino , Humanos , Modelos Lineares , Mamografia , Pessoa de Meia-Idade , Análise Multivariada , Risco , Inquéritos e Questionários , Estados Unidos/epidemiologia
11.
Anticancer Res ; 40(4): 2303-2309, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32234930

RESUMO

BACKGROUND/AIM: To predict pCR during neoadjuvant chemotherapy is still difficult. The aim of this study was to evaluate the optimal tumor reduction rate and modalities for predicting pCR after two cycles of docetaxel. PATIENTS AND METHODS: We analyzed 52 patients with HER2-positive or triple-negative breast cancer. The tumor reduction rate was evaluated after two 3-week cycles of docetaxel (plus trastuzumab for HER2-positive cancer patients). Patients without progression completed two additional cycles of docetaxel and four cycles of an anthracycline-containing regimen. RESULTS: Twenty-eight patients achieved pCR. The optimal tumor reduction rates for predicting pCR were 23, 39, 32, and 40% for US, caliper, MMG, and MRI measurements, respectively. The AUC was highest for caliper measurements. The optimal modality for predicting pCR differed among subtypes. CONCLUSION: Although tumor reduction rate after two cycles of chemotherapy is highly predictive of pCR, the optimal cutoff value differed among the modalities and breast cancer subtype.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Mama/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Adulto , Antraciclinas/administração & dosagem , Mama/diagnóstico por imagem , Mama/patologia , Neoplasias da Mama/metabolismo , Docetaxel/administração & dosagem , Esquema de Medicação , Feminino , Humanos , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Terapia Neoadjuvante , Receptor ErbB-2/metabolismo , Indução de Remissão , Trastuzumab/administração & dosagem , Carga Tumoral/efeitos dos fármacos , Ultrassonografia
12.
Plast Reconstr Surg ; 145(6): 1357-1365, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32195862

RESUMO

BACKGROUND: Breast reconstruction in patients with a high body mass index (BMI) (≥30 kg/m) is technically challenging and is associated with increased postoperative complications. The optimal reconstructive approach for these patients remains to be determined. This study compared outcomes of prepectoral and dual-plane reconstruction in high-BMI patients to determine whether there was an association between postoperative complications and the plane of reconstruction. METHODS: High-BMI patients who underwent immediate dual-plane or prepectoral expander/implant reconstruction were included in this retrospective study. Patients were stratified by reconstructive approach (dual-plane or prepectoral), and postoperative complications were compared between the groups. Multivariate logistic regression analysis was performed to determine whether the plane of reconstruction was an independent predictor of any complication after adjusting for potential confounding differences in patient variables between the groups. RESULTS: Of 133 patients, 65 (128 breasts) underwent dual-plane and 68 (129 breasts) underwent prepectoral reconstruction. Rates of seroma (13.3 percent versus 3.1 percent), surgical-site infection (9.4 percent versus 2.3 percent), capsular contracture (7.0 percent versus 0.8 percent), and any complication (25.8 percent versus 14.7 percent) were significantly higher in patients who had dual-plane versus prepectoral reconstruction (p < 0.05). Multivariate logistic regression identified dual-plane, diabetes, neoadjuvant radiotherapy, and adjuvant chemotherapy as significant, independent predictors of any complication (p < 0.05). Dual-plane reconstruction increased the odds of any complication by 3-fold compared with the prepectoral plane. CONCLUSION: Compared with the dual-plane approach, the prepectoral approach appears to be associated with a lower risk of postoperative complications following immediate expander/implant breast reconstruction and may be a better reconstructive option in high-BMI patients. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.


Assuntos
Índice de Massa Corporal , Neoplasias da Mama/terapia , Mamoplastia/métodos , Mastectomia/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Adulto , Idoso , Mama/efeitos dos fármacos , Mama/efeitos da radiação , Mama/cirurgia , Implantes de Mama/efeitos adversos , Quimioterapia Adjuvante/efeitos adversos , Estética , Feminino , Humanos , Mamoplastia/efeitos adversos , Mamoplastia/instrumentação , Pessoa de Meia-Idade , Terapia Neoadjuvante/efeitos adversos , Terapia Neoadjuvante/métodos , Seleção de Pacientes , Músculos Peitorais/transplante , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Radioterapia Adjuvante/efeitos adversos , Estudos Retrospectivos , Fatores de Risco , Dispositivos para Expansão de Tecidos/efeitos adversos
13.
PLoS One ; 15(2): e0228945, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32040528

RESUMO

Recent studies indicated that intramammary administration of active vitamin D3 hormone (1,25D3) inhibits the inflammatory process associated with mastitis. We hypothesized that attenuation of endoplasmic reticulum (ER) stress by 1,25D3 in mammary epithelial cells (MECs) is an important cellular mechanism contributing to this beneficial effect of intramammary treatment with 1,25D3. To test this hypothesis, the effect of 1,25D3 was studied on induction of ER stress in a transformed human MEC line, MCF-7 cells. Treatment with two different ER stress inducers, thapsigargin (TG) and tunicamycin (TM), caused a dose-dependent induction of ER stress as evident from up-regulation of protein kinase RNA-like ER kinase (PERK), heat shock protein family A (Hsp70) member 5 (HSPA5), activating transcription factor (ATF4), ATF6, DNA damage inducible transcript 3 (DDIT3) and spliced X-box binding protein 1 (sXBP1) and impaired cell viability and decreased expression of vitamin D receptor (VDR) in MCF-7 cells (P < 0.05). Treatment with 1,25D3 (100 nM) inhibited TG (10 nM)- and TM (1 µg/mL)-induced mRNA and/or protein levels of ATF4, ATF6, DDIT3 and HSPA5 in MCF-7 cells (P < 0.05). In addition, 1,25D3 (100 nM) antagonized the effect of TG (10 nM) and TM (1 µg/mL) on mRNA and protein levels of VDR and mRNA levels of genes involved in production and degradation of 1,25D3 in MCF-7 cells (P < 0.05). Moreover, 1,25D3 (100 nM) inhibited nuclear factor-κB (NF-κB) activation in response to TM (10 nM) and TG (1 µg/mL) in MCF-7 cells. In conclusion, the present findings show that 1,25D3 is effective in attenuating ER stress and the NF-κB-driven inflammatory response in MCF-7 cells. This indicates that attenuation of ER stress by 1,25D3 in MECs may contribute to the recently observed inhibitory effect of intramammary treatment of dairy cows with 1,25D3 on the inflammatory process associated with mastitis.


Assuntos
Mama/efeitos dos fármacos , Mama/metabolismo , Calcitriol/farmacologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Animais , Mama/patologia , Calcitriol/metabolismo , Bovinos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Feminino , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Células MCF-7 , Mastite/tratamento farmacológico , Mastite/metabolismo , Mastite/patologia , Mastite Bovina/tratamento farmacológico , Mastite Bovina/metabolismo , Mastite Bovina/patologia , NF-kappa B/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Tapsigargina/toxicidade , Tunicamicina/toxicidade
14.
Nat Commun ; 11(1): 385, 2020 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-31959756

RESUMO

The HER2-enriched (HER2-E) subtype within HER2-positive (HER2+) breast cancer is highly addicted to the HER2 pathway. However, ∼20-60% of HER2+/HER2-E tumors do not achieve a complete response following anti-HER2 therapies. Here we evaluate gene expression data before, during and after neoadjuvant treatment with lapatinib and trastuzumab in HER2+/HER2-E tumors of the PAMELA trial and breast cancer cell lines. Our results reveal that dual HER2 blockade in HER2-E disease induces a low-proliferative Luminal A phenotype both in patient's tumors and in vitro models. These biological changes are more evident in hormone receptor-positive (HR+) disease compared to HR-negative disease. Interestingly, increasing the luminal phenotype with anti-HER2 therapy increased sensitivity to CDK4/6 inhibition. Finally, discontinuation of HER2-targeted therapy in vitro, or acquired resistance to anti-HER2 therapy, leads to restoration of the original HER2-E phenotype. Our findings support the use of maintenance anti-HER2 therapy and the therapeutic exploitation of subtype switching with CDK4/6 inhibition.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/tratamento farmacológico , Mama/patologia , Receptor ErbB-2/metabolismo , Adulto , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/imunologia , Biópsia , Mama/efeitos dos fármacos , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Perfilação da Expressão Gênica , Humanos , Lapatinib/farmacologia , Lapatinib/uso terapêutico , Terapia Neoadjuvante/métodos , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/imunologia , Trastuzumab/farmacologia , Trastuzumab/uso terapêutico , Resultado do Tratamento
15.
Cancer Lett ; 472: 165-174, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31857156

RESUMO

Tumor-targeted drug delivery systems with stimuli-response drug release have been increasingly used to improve the therapeutic efficacy of antitumor drugs. Here, we report a specific molecular recognition activation drug nanoplatform based on specially designed DNA sensor-capped doxorubicin (DOX)-loaded mesoporous silica nanoparticles (MSNs), designated as specific molecular recognition-activated nanoparticle (SMRAN). DNA sensors on the targeted nanoparticles can trigger DOX release through a conformational switch induced by MUC-1. This causes a significant difference in cell viability between breast cancer MCF-7 and normal breast Hs578bst cells (24.8% and 86.0%). In vivo experiments showed that the tumor volume was reduced 1.5-times in the SMRAN treatment group. Compared with that in the DOX group, due to significantly improved tumor accumulation and retention of DOX. The strategy of the MUC-1 activated drug delivery system is expected to provide a new perspective for clinical application.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Mucina-1/genética , Nanopartículas/química , Mama/efeitos dos fármacos , Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Adutos de DNA/química , Adutos de DNA/farmacologia , Doxorrubicina/química , Doxorrubicina/farmacologia , Portadores de Fármacos , Liberação Controlada de Fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Células MCF-7
16.
Biochim Biophys Acta Mol Basis Dis ; 1866(1): 165561, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31639439

RESUMO

Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype with few therapy options besides chemotherapy. Although platinum-based drugs have shown initial activity in BRCA1-mutated TNBCs, chemoresistance remains a challenge. Here we show that RAD6B (UBE2B), a principal mediator of translesion synthesis (TLS), is overexpressed in BRCA1 wild-type and mutant TNBCs, and RAD6B overexpression correlates with poor survival. Pretreatment with a RAD6-selective inhibitor, SMI#9, enhanced cisplatin chemosensitivity of BRCA1 wild-type and mutant TNBCs. SMI#9 attenuated cisplatin-induced PCNA monoubiquitination (TLS marker), FANCD2 (Fanconi anemia (FA) activation marker), and TLS polymerase POL η. SMI#9-induced decreases in γH2AX levels were associated with concomitant inhibition of H2AX monoubiquitination, suggesting a key role for RAD6 in modulating cisplatin-induced γH2AX via H2AX monoubiquitination. Concordantly, SMI#9 inhibited γH2AX, POL η and FANCD2 foci formation. RAD51 foci formation was unaffected by SMI#9, however, its recruitment to double-strand breaks was inhibited. Using the DR-GFP-based assay, we showed that RAD6B silencing or SMI#9 treatment impairs homologous recombination (HR) in HR-proficient cells. DNA fiber assays confirmed that restart of cisplatin-stalled replicating forks is inhibited by SMI#9 in both BRCA1 wild-type and mutant TNBC cells. Consistent with the in vitro data, SMI#9 and cisplatin combination treatment inhibited BRCA1 wild-type and mutant TNBC growth as compared to controls. These RAD6B activities are unaffected by BRCA1 status of TNBCs suggesting that the RAD6B function in TLS/FA crosstalk could occur in HR-dependent and independent modes. Collectively, these data implicate RAD6 as an important therapeutic target for TNBCs irrespective of their BRCA1 status.


Assuntos
Antineoplásicos/farmacologia , Proteína BRCA1/metabolismo , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Anemia de Fanconi/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Enzimas de Conjugação de Ubiquitina/metabolismo , Mama/efeitos dos fármacos , Mama/metabolismo , Linhagem Celular Tumoral , Dano ao DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Replicação do DNA/efeitos dos fármacos , Feminino , Células HeLa , Humanos , Ubiquitinação/efeitos dos fármacos
17.
Cancer Biomark ; 27(1): 11-17, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31640083

RESUMO

BACKGROUND: Novel biomarkers are needed to predict the effectiveness of the treatment of presurgical neoadjuvant chemotherapy (NAC) in breast cancer (BC). OBJECTIVE: This is an exploratory study to assess the impact of 3 cancer-related long non-coding RNAs (lncRNAs) (H19, MALAT1 and GA5) in blood plasma of patients with BC in predicting the response to NAC. METHODS: The plasma levels of RNAs were relatively measured by quantitative PCR at baseline, and at the end of the fourth cycle of NAC in patients with locally advanced BC. RESULTS: Only H19 was associated with patients' characteristics, and with the response to NAC. Higher plasma expression of H19 was associated with younger age at diagnosis, triple negative tumors, and Ki-67 index. Patients with a pathological complete response (20%) had lower pre-therapeutic levels of H19 compared with the non-complete responders (relative levels 0.1 vs 0.2, respectively, P: 0.04). In addition, the patients with higher degree of downstaging of initial tumors had lower baseline levels of H19 among non-complete responders. CONCLUSION: Our study reveals that H19, but not MALAT1 and GAS5, may be a useful marker of response to NAC in BC.


Assuntos
Neoplasias da Mama/tratamento farmacológico , RNA Longo não Codificante/sangue , Adulto , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Mama/efeitos dos fármacos , Mama/patologia , Neoplasias da Mama/sangue , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Antígeno Ki-67/sangue , Biópsia Líquida , Pessoa de Meia-Idade , Terapia Neoadjuvante , Paclitaxel/administração & dosagem , RNA Longo não Codificante/genética
18.
Cancer ; 126(1): 181-188, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31454422

RESUMO

BACKGROUND: There is a controversy about late-onset congestive heart failure (CHF) among breast cancer survivors. This study investigated the incidence rate and risk factors of late-onset CHF more than 2 years after the breast cancer diagnosis. METHODS: A nationwide, retrospective study was conducted with the National Health Information Database. With 1:3 age- and sex-matched noncancer controls, Cox proportional hazard regression models were used to analyze the incidence and risk factors of late CHF. The cumulative incidence rate of late CHF was evaluated with a Kaplan-Meier analysis and a log-rank test. RESULTS: A total of 91,227 cases (286,480 person-years) and 273,681 controls (884,349 person-years) were evaluated between January 2007 and December 2013. The risks of late CHF were higher in cases than controls (hazard ratio [HR], 1.396; 95% confidence interval [CI], 1.268-1.538). Younger survivors (age ≤ 50 years) showed a higher risk of late CHF than their younger counterparts (HR, 2.903; 95% CI, 2.425-3.474). Although older age was a risk factor for late CHF, older survivors (age ≥ 66 years) showed no difference in the risk of late CHF in comparison with their counterparts (HR, 0.906; 95% CI, 0.757-1.084). Anthracyclines and taxanes were risk factors for late CHF, although trastuzumab, radiation, and endocrine therapy were not. CONCLUSIONS: Young breast cancer survivors have a greater risk of late CHF than the young population without cancer. More attention should be paid to young breast cancer survivors who receive taxane- or anthracycline-based regimens over the long term.


Assuntos
Antineoplásicos/efeitos adversos , Neoplasias da Mama/epidemiologia , Sobreviventes de Câncer , Insuficiência Cardíaca/epidemiologia , Adulto , Idoso , Antraciclinas/efeitos adversos , Mama/efeitos dos fármacos , Mama/patologia , Neoplasias da Mama/complicações , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Hidrocarbonetos Aromáticos com Pontes/efeitos adversos , Quimioterapia Adjuvante/efeitos adversos , Feminino , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/patologia , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Medição de Risco , Fatores de Risco , Taxoides/efeitos adversos , Trastuzumab/efeitos adversos
19.
Support Care Cancer ; 28(3): 1481-1489, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31273506

RESUMO

PURPOSE: We conducted a randomized, double-blind, vehicle-controlled clinical trial to investigate the use of a new proprietary hyaluronan (HA) formulation for the prevention of acute skin toxicity in breast cancer patients undergoing radiotherapy (RT). METHODS: Thirty women with breast cancer undergoing whole breast RT were enrolled. Each patient was randomly assigned to HA formulation (study cream, S) on the medial or lateral half of the irradiated breast and the control cream (placebo, P) on the other half. The primary endpoint was physician's evaluation of skin symptoms at week 5 during RT and week 2 post-RT. We also collected patients' independent assessment of skin after RT, patient's product preference, and an independent physician panel assessment of skin reactions based on photographs. RESULTS: Twenty-eight patients were evaluable. On physician's evaluation, there was no significant difference in radiation dermatitis between S and P and no overall preference to either cream at week 5 during or week 2 post-RT. More patients preferred S in evaluating skin appearance and skin reactions, but this did not reach statistical significance. Univariate analysis showed that physicians had an overall preference to the S cream at week 2 post-RT in patients with larger breasts. On the independent panel assessment, 3 reviewers saw no significant difference in radiation toxicity, whereas one reviewer reported better skin outcome with S cream at week 5. CONCLUSIONS: We found a nonstatistically significant patient preference but overall no significant radioprotective effects for this HA formulation compared with placebo except in patients with larger breasts. TRIAL REGISTRATION: The study was registered at www.clinicaltrials.gov (NCT02165605).


Assuntos
Neoplasias da Mama/radioterapia , Mama/anormalidades , Ácido Hialurônico/uso terapêutico , Hipertrofia/prevenção & controle , Lesões por Radiação/prevenção & controle , Radiodermatite/prevenção & controle , Adulto , Idoso , Mama/efeitos dos fármacos , Mama/efeitos da radiação , Método Duplo-Cego , Feminino , Humanos , Pessoa de Meia-Idade , Pomadas , Radiodermatite/tratamento farmacológico , Pele/patologia , Pele/efeitos da radiação
20.
J Surg Res ; 247: 52-58, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31787317

RESUMO

BACKGROUND: Metformin use has been linked to pathologic complete response (pCR) following neoadjuvant chemotherapy for several malignancies. We aimed to investigate the association of diabetes mellitus (DM) and metformin use with pCR in breast cancer. MATERIALS AND METHODS: All breast cancer patients who received neoadjuvant chemotherapy during June 2013-October 2016 at two academic medical centers were identified. A retrospective cohort study evaluated patients who did and did not achieve pCR. Multivariable logistic regression identified independent predictors of pCR, specifically looking at metformin use and DM. RESULTS: The study group included 351 breast cancer patients, with 90 (25.6%) achieving pCR after neoadjuvant chemotherapy. The rate of DM did not differ between those with and without pCR, nor did the rate of metformin use. Multivariable logistic regression identified HER2-positive tumors and smaller preoperative tumor size as predictors of pCR. The estrogen receptor (ER) positivity was associated with an absence of pCR. Importantly, neither DM nor metformin use was predictive of pCR. CONCLUSIONS: This study by the two institutions supports previous data of tumor-related factors known to be associated with pCR; however, the current analysis found neither DM nor metformin to be independently associated with pCR. Thus, additional prospective study is warranted prior to validating metformin as an antitumor agent.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/terapia , Diabetes Mellitus Tipo 2/epidemiologia , Metformina/administração & dosagem , Terapia Neoadjuvante/métodos , Adulto , Idoso , Mama/efeitos dos fármacos , Mama/patologia , Mama/cirurgia , Neoplasias da Mama/complicações , Neoplasias da Mama/patologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Humanos , Mastectomia , Pessoa de Meia-Idade , Terapia Neoadjuvante/estatística & dados numéricos , Prognóstico , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Estudos Retrospectivos , Resultado do Tratamento
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